fmqxd 3/16/04 AM Page i a LANGE medical book Harper's Illustrated Biochemistry twenty-sixth edition Robert K. Murray, MD, PhD Professor (Emeritus ). Harper's Illustrated Biochemistry, Twenty-Sixth Edition , the third edition appeared with Harold A. Harper, University of California School of Medicine at. Harper's Illustrated Biochemistry 26th Edition. Integrating detailed discussions of biochemical diseases, updated clinical information, case studies, and extensive.

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Harper's Biochemistry 26th ED, Schemes and Mind Maps for Medical Biochemistry Harper's Illustrated Biochemistry, Twenty-Sixth Edition. a LANGE medical book. Harper's Illustrated. Biochemistry. Twenty-Eighth Edition. Robert K. Murray, MD, PhD. Professor (Emeritus) of Biochemistry. University of. Harpers Illustrated Biochemistry – 26th Edition [PDF]. Harpers Illustrated Biochemistry - 26th Edition [PDF]. 8 MB PDF.

The results are having major effects on areas such as proteomics, bioinformatics, biotechnology, and pharmacogenomics. Reference to the human genome will be made in various sections of this text. The Human Genome Project is discussed in more detail in Chapter Because life depends on biochemical reactions, biochemistry has become the basic language of all biologic sci- ences.

Health depends on a harmonious balance of bio- chemical reactions occurring in the body, and disease reflects abnormalities in biomolecules, biochemical reactions, or biochemical processes. Conversely, the study of diseases has often revealed previously unsuspected aspects of biochemistry. The determination of the se- quence of the human genome, nearly complete, will have a great impact on all areas of biology, including biochemistry, bioinformatics, and biotechnology.

Fruton JS: Proteins, Enzymes, Genes: The Interplay of Chemistry and Biology. Yale Univ Press, International Human Genome Sequencing Consortium.

Initial se- quencing and analysis of the human genome. Nature The issue [15 February] consists of articles dedicated to analyses of the human genome.

McKusick VA: Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders, 12th ed. Johns Hopkins Univ Press, The online version is updated al- most daily. Scriver CR et al editors: McGraw-Hill, Venter JC et al: The Sequence of the Human Genome. Science ; The issue [16 February] contains the Celera draft version and other articles dedicated to analyses of the human genome. Williams DL, Marks V: Scientific Foundations of Biochemistry in Clinical Practice, 2nd ed.

Butterworth-Heinemann, Water is the predominant chemical component of liv- ing organisms. The manner in which water interacts with a sol- vated biomolecule influences the structure of each. An excellent nucleophile, water is a reactant or product in many metabolic reactions.

Water has a slight propensity to dissociate into hydroxide ions and protons. The acidity of aqueous solutions is generally reported using the logarithmic pH scale. Bicarbonate and other buffers normally maintain the pH of extracellular fluid be- tween 7.

Suspected disturbances of acid- base balance are verified by measuring the pH of arter- ial blood and the CO2 content of venous blood. Regu- lation of water balance depends upon hypothalamic mechanisms that control thirst, on antidiuretic hor- mone ADH , on retention or excretion of water by the kidneys, and on evaporative loss.


Nephrogenic diabetes insipidus, which involves the inability to concentrate urine or adjust to subtle changes in extracellular fluid osmolarity, results from the unresponsiveness of renal tubular osmoreceptors to ADH. A water molecule is an irregular, slightly skewed tetra- hedron with oxygen at its center Figure 2—1. The two hydrogens and the unshared electrons of the remaining two sp 3-hybridized orbitals occupy the corners of the tetrahedron. The degree angle between the hydro- gens differs slightly from the ideal tetrahedral angle, Ammonia is also tetrahedral, with a degree angle between its hydrogens.

Water is a dipole, a molecule with electrical charge distributed asymmetri- cally about its structure. The strongly electronegative. Water, a strong dipole, has a high dielectric con- stant. The di- electric constant for a vacuum is unity; for hexane it is 1. Water therefore greatly decreases the force of attraction between charged and polar species relative to water-free environments with lower dielectric constants. Its strong dipole and high dielectric constant enable water to dis- solve large quantities of charged compounds such as salts.

An unshielded hydrogen nucleus covalently bound to an electron-withdrawing oxygen or nitrogen atom can interact with an unshared electron pair on another oxy- gen or nitrogen atom to form a hydrogen bond. Since water molecules contain both of these features, hydro- gen bonding favors the self-association of water mole- cules into ordered arrays Figure 2—2.

Hydrogen bond- ing profoundly influences the physical properties of water and accounts for its exceptionally high viscosity, surface tension, and boiling point. On average, each molecule in liquid water associates through hydrogen bonds with 3. These bonds are both relatively weak and transient, with a half-life of about one mi- crosecond.

Rupture of a hydrogen bond in liquid water requires only about 4. Hydrogen bonding enables water to dissolve many organic biomolecules that contain functional groups which can participate in hydrogen bonding. The oxy- gen atoms of aldehydes, ketones, and amides provide pairs of electrons that can serve as hydrogen acceptors. Alcohols and amines can serve both as hydrogen accep- tors and as donors of unshielded hydrogen atoms for formation of hydrogen bonds Figure 2—3.

Figure 2—2. Association of two dipolar water molecules by a hydrogen bond dotted line. Hydrogen-bonded cluster of four water molecules. Note that water can serve simultaneously both as a hy- drogen donor and as a hydrogen acceptor.

Figure 2—3. Additional polar groups participate in hydrogen bonding. Shown are hydrogen bonds formed between an alcohol and water, between two molecules of ethanol, and between the peptide carbonyl oxygen and the peptide nitrogen hydrogen of an adjacent amino acid.

The covalent bond is the strongest force that holds molecules together Table 2—1. Noncovalent forces, while of lesser magnitude, make significant contribu- tions to the structure, stability, and functional compe- tence of macromolecules in living cells. These forces, which can be either attractive or repulsive, involve in- teractions both within the biomolecule and between it and the water that forms the principal component of the surrounding environment. Most biomolecules are amphipathic; that is, they pos- sess regions rich in charged or polar functional groups as well as regions with hydrophobic character.

Proteins tend to fold with the R-groups of amino acids with hy- drophobic side chains in the interior. Amino acids with charged or polar amino acid side chains eg, arginine, glutamate, serine generally are present on the surface in contact with water.

A similar pattern prevails in a phospholipid bilayer, where the charged head groups of. This pattern maxi- mizes the opportunities for the formation of energeti- cally favorable charge-dipole, dipole-dipole, and hydro- gen bonding interactions between polar groups on the biomolecule and water. It also minimizes energetically unfavorable contact between water and hydrophobic groups. Hydrophobic interaction refers to the tendency of non- polar compounds to self-associate in an aqueous envi- ronment.

While the hydrogens of nonpolar groups such as the methylene groups of hydrocarbons do not form hydro- gen bonds, they do affect the structure of the water that surrounds them. Water molecules adjacent to a hy- drophobic group are restricted in the number of orien- tations degrees of freedom that permit them to par- ticipate in the maximum number of energetically favorable hydrogen bonds. Maximal formation of mul- tiple hydrogen bonds can be maintained only by in- creasing the order of the adjacent water molecules, with a corresponding decrease in entropy.

It follows from the second law of thermodynamics that the optimal free energy of a hydrocarbon-water mixture is a function of both maximal enthalpy from hydrogen bonding and minimum entropy maximum degrees of freedom. Thus, nonpolar molecules tend to form droplets with minimal exposed surface area, re- ducing the number of water molecules affected. For the same reason, in the aqueous environment of the living cell the hydrophobic portions of biopolymers tend to be buried inside the structure of the molecule, or within a lipid bilayer, minimizing contact with water.

Interactions between charged groups shape biomolecu- lar structure. Electrostatic interactions between oppo- sitely charged groups within or between biomolecules are termed salt bridges. Salt bridges are comparable in strength to hydrogen bonds but act over larger dis- tances.

They thus often facilitate the binding of charged molecules and ions to proteins and nucleic acids. Van der Waals forces arise from attractions between transient dipoles generated by the rapid movement of electrons on all neutral atoms. Significantly weaker than hydrogen bonds but potentially extremely numer- ous, van der Waals forces decrease as the sixth power of the distance separating atoms. The DNA double helix illustrates the contribution of multiple forces to the structure of biomolecules.

While each individual DNA strand is held together by cova- lent bonds, the two strands of the helix are held to- gether exclusively by noncovalent interactions. These noncovalent interactions include hydrogen bonds be- tween nucleotide bases Watson-Crick base pairing and van der Waals interactions between the stacked purine and pyrimidine bases.

The helix presents the charged phosphate groups and polar ribose sugars of. The extended back- bone maximizes the distance between negatively charged backbone phosphates, minimizing unfavorable electrostatic interactions.

Metabolic reactions often involve the attack by lone pairs of electrons on electron-rich molecules termed nucleophiles on electron-poor atoms called elec- trophiles. Nucleophiles and electrophiles do not neces- sarily possess a formal negative or positive charge.

Water, whose two lone pairs of sp 3 electrons bear a par- tial negative charge, is an excellent nucleophile. Other nucleophiles of biologic importance include the oxygen atoms of phosphates, alcohols, and carboxylic acids; the sulfur of thiols; the nitrogen of amines; and the imid- azole ring of histidine. Common electrophiles include the carbonyl carbons in amides, esters, aldehydes, and ketones and the phosphorus atoms of phosphoesters.

Nucleophilic attack by water generally results in the cleavage of the amide, glycoside, or ester bonds that hold biopolymers together. This process is termed hy- drolysis. Conversely, when monomer units are joined together to form biopolymers such as proteins or glyco- gen, water is a product, as shown below for the forma- tion of a peptide bond between two amino acids.

While hydrolysis is a thermodynamically favored re- action, the amide and phosphoester bonds of polypep- tides and oligonucleotides are stable in the aqueous en- vironment of the cell. This seemingly paradoxic behavior reflects the fact that the thermodynamics gov- erning the equilibrium of a reaction do not determine the rate at which it will take place.

In the cell, protein catalysts called enzymes are used to accelerate the rate. Proteases catalyze the hydrolysis of proteins into their component amino acids, while nucleases catalyze the hydrolysis of the phosphoester bonds in DNA and RNA. Careful control of the activities of these enzymes is required to ensure that they act only on appropriate target molecules.

In group transfer reactions, a group G is transferred from a donor D to an acceptor A, forming an acceptor group complex A—G:. The hydrolysis and phosphorolysis of glycogen repre- sent group transfer reactions in which glucosyl groups are transferred to water or to orthophosphate. The equilibrium constant for the hydrolysis of covalent bonds strongly favors the formation of split products.

The biosynthesis of macromolecules also involves group transfer reactions in which the thermodynamically un- favored synthesis of covalent bonds is coupled to fa- vored reactions so that the overall change in free energy favors biopolymer synthesis.

Given the nucleophilic character of water and its high concentration in cells, why are biopolymers such as proteins and DNA rela- tively stable? And how can synthesis of biopolymers occur in an apparently aqueous environment? Central to both questions are the properties of enzymes. In the absence of enzymic catalysis, even thermodynamically highly favored reactions do not necessarily take place rapidly.

Precise and differential control of enzyme ac- tivity and the sequestration of enzymes in specific or- ganelles determine under what physiologic conditions a given biopolymer will be synthesized or degraded.

Harper's Biochemistry 26th ED, Schemes and Mind Maps for Medical Biochemistry

Newly synthesized polymers are not immediately hy- drolyzed, in part because the active sites of biosynthetic enzymes sequester substrates in an environment from which water can be excluded. The ability of water to ionize, while slight, is of central importance for life. The transferred proton is actually associated with a cluster of water molecules.

Since hydronium and hydroxide ions continuously recombine to form water molecules, an individual hy- drogen or oxygen cannot be stated to be present as an ion or as part of a water molecule. At one instant it is an ion.

Harper’s Illustrated Biochemistry 26th Edition

An instant later it is part of a molecule. Individ- ual ions or molecules are therefore not considered. We refer instead to the probability that at any instant in time a hydrogen will be present as an ion or as part of a water molecule.

Since 1 g of water contains 3. To state that the probability that a hydrogen exists as an ion is 0. The actual probability of a hydrogen atom in pure water existing as a hydrogen ion is approximately 1. The proba- bility of its being part of a molecule thus is almost unity.

Stated another way, for every hydrogen ion and hydroxyl ion in pure water there are 1. Hydrogen ions and hydroxyl ions nevertheless contribute significantly to the properties of water. Pure water thus is Since the probability that a hydrogen in pure water will exist as a hydrogen ion is 1.

The result is 1. The molar concentration of water, It therefore is considered to be essentially constant. This constant may then be incorporated into the dissociation constant K to provide a useful new constant K w termed the ion product for water. The relationship between K w and K is shown below:. Within the stated limitations of the effect of tem- perature, Kw equals We shall use K w to calculate the pH of acidic and basic solutions.

This definition, while not rigorous, suffices for many biochemical purposes. To calculate the pH of a solution:. Acids are proton donors and bases are proton ac- ceptors.

Weak acids dissociate only partially in acidic solutions. Many biochemicals are weak acids. Exceptions include phosphorylated in-. Example 1: What is the pH of a solution whose hy- drogen ion concentration is 3. Example 2: What is the pH of a solution whose hy- droxide ion concentration is 4. Example 3: What are the pH values of a 2. The same cannot be said for the second case b:. Molarity of KOH 2. Once a decision has been reached about the significance of the contribution by water, pH may be calculated as above.

This assumption is valid for dilute solutions of strong bases or acids but not for weak bases or acids. Many biochemicals possess functional groups that are weak acids or bases.

Carboxyl groups, amino groups, and the second phosphate dissociation of phosphate es- ters are present in proteins and nucleic acids, most coenzymes, and most intermediary metabolites. Knowl- edge of the dissociation of weak acids and bases thus is basic to understanding the influence of intracellular pH on structure and biologic activity. Charge-based separa- tions such as electrophoresis and ion exchange chro- matography also are best understood in terms of the dissociation behavior of functional groups.

Representative weak acids left , their conjugate bases center , and the p K a values right include the following:. Full Text. Murray R. Figures from Harper's Biochemistry, 25th Edition The free radical of ribonucleotide reductase The initial free radical is generated via a dinuclear.

Delphi Xe2 Update 4 Hotfix 1 Crack weakly. Well, Id better go. There's a feast, and my friend Hermione should be awake by now Dobby threw his arms around Harry's middle and hugged him. Harry Potter is greater by far than Dobby knew! Farewell, Harry Potter! This asymmetric behavior is due to channeling— transfer of the product of citrate synthase directly onto the active site of aconitase without entering free solution.

This provides integration of citric acid cycle activity and the provision of citrate in the cytosol as a source of acetyl-CoA for fatty acid synthesis.

The poison fluoroacetate is toxic because fluoroacetyl-CoA condenses with oxaloacetate to form fluorocitrate, which inhibits aconitase, causing citrate to accumulate. In the subsequent reactions, two molecules of CO2 are released and oxaloacetate is regenerated Figure 16—1.

Only a small quantity of oxaloacetate is needed for the oxidation of a large quantity of acetyl-CoA; oxaloacetate may be considered to play a catalytic role. The citric acid cycle is an integral part of the process by which much of the free energy liberated during the oxidation of fuels is made available.

During oxidation of acetyl-CoA, coenzymes are reduced and subsequently reoxidized in the respiratory chain, linked to the formation of ATP oxidative phosphorylation; see Figure 16—2 and also Chapter This process is aerobic, requiring oxygen as the final oxidant of the reduced coenzymes. The enzymes of the citric acid cycle are lo Tissues in which gluconeogenesis occurs the liver and kidney contain two isoenzymes of succinate thiokinase.

The equilibrium of this reaction is so much in favor of succinyl-CoA formation that it must be considered physiologically unidirectional. This is the only example in the citric acid cycle of substrate-level phosphorylation.

Harper's Illustrated Biochemistry( 26th Ed, 2003)

As in the case of pyruvate oxidation Chapter The citric acid cycle: Succinyl-CoA is converted to succinate by the enzyme succinate thiokinase succinyl-CoA synthetase. The GTP formed is used for the decarboxylation of oxaloacetate to phosphoenolpyruvate in gluconeogenesis and provides a regulatory link between citric acid cycle activity and the withdrawal of oxaloacetate for gluconeogenesis. There are three isoenzymes of isocitrate dehydrogenase.

Citric acid cycle. P are generated via oxFor one turn of the cycle. Nongluconeogenic tissues have only the isoenzyme that uses ADP. For a discussion of the stereochemical aspects of the citric acid cycle. In order to follow the passage of acetyl-CoA through the cycle.

Although two carbon atoms are lost as CO2 in one revolution of the cycle. Reactions of the citric acid Krebs cycle. Because succinate is a symmetric compound and because succinate dehydrogenase does not differentiate between its two carboxyl groups. During gluconeogenesis.

The enzyme contains FAD and iron-sulfur Fe: S protein and directly reduces ubiquinone in the respiratory chain. Because it functions in both oxidative and synthetic processes. Malate is converted to oxaloacetate by malate dehydrogenase. Fumarase fumarate hydratase catalyzes the addition of water across the double bond of fumarate.


Although the equilibrium of this reaction strongly favors malate. This reaction is important in maintaining an adequate concentration of oxaloacetate for the condensation reaction with acetyl-CoA. These reducing equivalents are transferred to the respiratory chain Figure 16—2. Aminotransferase transaminase reactions form pyruvate from alanine. The onward metabolism of succinate. The first dehydrogenation reaction. Net transfer into the cycle occurs as a result of several different reactions.

The key enzyme that catalyzes net transfer out of the cycle into gluconeogenesis is phosphoenolpyruvate carboxykinase. It also provides the substrates for amino acid synthesis by transamination. In addition. Because these reactions are reversible. If acetylCoA accumulates.This process is termed hy- drolysis.

Science ; The chapters that are poorly written make it difficult to nail down the main points. Figure 2—3.

Well, Id better go. We may as The content of this module cannot be visible by unauthenticated users. Figure 1—1.

However, most first year med students are not biochem majors and need a text that is easier to read and enjoy. The degree angle between the hydro- gens differs slightly from the ideal tetrahedral angle,